Indian Patents
Title of Invention

QUINOLINONE / BENZOXAZINONE DERIVATIVES
Abstract The invention provides compounds of the formula: (I) and pharmaceutically acceptable salts or prodrugs thereof, wherein m, p, q, r, A, E, X, Y, R<SUP>1</SUP>, R<SUP>4</SUP>, R<SUP>5</SUP> , R<SUP>6</SUP>, R<SUP>7</SUP>, R<SUP>8</SUP> , R<SUP>9</SUP> and are as defined herein. The invention also provides methods for preparing, compositions comprising, and methods for using compounds of formula I.
Full Text This invention rektes to substituted benzoxazinone compounds, and associated compositions, methods for use as therapeutic agents, and methods of preparation
thereof.
The actions of tiie neurotransmitter 5-hydroxytryptamine (5-HT) as a major modulatory neurotransmitter in the brain, are mediated through, a number of receptor &milies termed 5-HTl, 5-HT2,5- HT3,5-HT4, 5-HT5, S-HTS, and 5-HT7. Based on a high level of 5-HT6 receptor mRNA in the brain, it has been stated that the 5-HT6 receptor may play a role in tiie pathology and treatment of central nerve system disorders. In particular, 5-HT6 sdedive ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson"s disease, Huntington"s disease, anxiety, depression, manic depression, psydioses, epilepsy, obsessive compxitsive disorders, migraine, Alzheimer"s disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Sudi compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorda:. See for example, BX. Roth et al., /. Pharmacol £xp. Ther., 1994,268> pages 1403-14120, D. R. Sibley et al., Mot Pharmacol, 1993,43,320-327, A.J. Sleight et al.. Neurotransmission, 1995,11,1-5, and A. J. Sleight et al.. Serotonin ID Research Alert, 1997,2(3), 115-8.
While some 5-HT6 modulators have been disclosed, there continues to be a need for compounds that are useful for modulating 5-HT6.
One objection of the present invention is (i) a compound of the formula:


and pharmaceutically acceptable salts or prodrugs thereof,
wherem:
m is from 0 to 4;
p is from 1 to 3;
q is from I to 3;
r is from 1 to 3;
A is optionally substituted arj^ene or optionally substituted heteroaryiene;
EisNorQ
X is 0, S, or -CR*R^- wherdn R" and R^ each ind^endenttf is hydrogen or alkyi;
each R^ independently is halo, alkji, haloalkyl, heteroallcyi, hydroxy, nitro, alkoxy, cyano, -S(0)^S -NR"R"", -CC=0)-HR"=R"^, -SOr-NR"R^-N(R"-C(=0)-R^ or _C(=0)-R^ wherein s is from 0 to 2 and R"^ and R*^ each independently is hydrogen or alkyi;
Y is -(CR^R^)n- wherein n is 1 or.2 and R^ and R^ each independently is hydrogen or alkyi, or X and Y together form an alkenylene group;
R^, R^ R^, R^, R^ and R" each independently is hydrogen or alkjd; and
R" is hydrogen, alkyi, arylalkyl, ar)doxyaIkyl, heteroaryl or heterocydyl.
(ii) The compoimd of (i), wherein said compound is of tiie formnla:


■wherda m, p, X, Y, E, R\ R\ R^ R", R^ R^ R^ R^ R" and R^" are as defined in
A is ar^ene or lieteroaryiene which are optionaJly substitiited by aUcyi, cycloaBcyi, cycIoaikyiaS^ heteroEjfcj^ hydroxyalfcyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylajniDO, di-aHcylamino, haloaHcyl, haloallcoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phen}^ car phenj^aJtyl), -(CR"R")n-COOR (where n is an
integer from 0 to 5, R" and R" are mdependently hydrogen or alfcyl, and R is hydrogen, alkyl cycloalkyl, cycloalkylallQ^ phenyl orphenylalkyi), or-(CR"R")n-CONR"""R^"
(where n is an integer fiom 0 to 5, R" and R" are independently hydrogen or alk>1, and R^" and R**" are, indepeudenliy of eadi othar, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyL
(iii) The compound of (ii), wherein said compound is of tie formula:

wherein X, Y, A, E, R\ R"°, m and n are as defined in (i). (iv) Tbe compound of (iii), wherein

SisOor-CHj-;
Y -(CH2)a- wiierem n is 1 or 2, or -X-Y- is -CH= Aisphenyien^indoljdene, orpTriimdinTienoptionaltysiibstitiitJedbytiie substituents according to (ii);
EisN;
K" is halogen, sUkaxf, and
R"* is hydrogen, aikyi,, aryiaflcfi, arjdoxyalkjd, heteroar^ or heterocydyL
(v) The compound of (iv), -whardn R^" is hydrogen, medij^, 2-(4-fliiorophaiyi)-etfayl, 2-(4-inethoxyphein"^)-ethyl. imidazolin-2-"^ or pyrimidin-2-7i; A is l,3-phen)^ene optionally substituted by the substituents according to (ii).
(vi) The compound of (v), wiierein A is halophenyiene, haloalkylphenyiene, aitjdphen^ene, alkoiyphen^iene or aDcjdenedioxyphen^ene.
(vii) The compound of (vi), wdierein said compound is sdected from the group consisting o£
l-{3-Pipera2iii- l-yi-ben2j4)-3,4-dihydra- lH-quinolin-2-one;
l-(4-Metiiosy-3-pipeTazin-l-^-beD27i)-3,4-dih7dro-lH-qmnolin-2-one;
l-(3-Chloro-5-piperazin-1 -j^-bexizj^)-3,4-dihydro-lH-quinolin-2-one;
l-(3-Methosy-5-pipera2in-l-^--benzyl)-3,4-dihydro-lH-qninolin-2-one;
6-C3iloro-l-{3-chloro-5-pipera2in-l -yi-benzj4) -3,4-dibydro- lH-quinDlin-2-one;
l-(3-C7dopentjdo27--5-piperaan-l-7l-ben2;jd)-3,4-dihydro-lH-quinoIiD-2-one;
l-(3-Hydroxy-5-pipera2m-l-)d--benzyi)-3,4-dihydro--lH-qmnoHn-2-one;.
l-(3-Ethosy-5-piperaan-l-"jd--benz^)-3,4-dih7dro-lH-quinalin-2-one;
l-[ 3-Methoxy-5- (4-metihylpipera2in-] -yl)-benzjd] -3,4-dih7dro-lH-qmnoHn-2-one;

l-(7-Pipera2in-l-7l-2,3-dih7dro-ben2o[l,4]diozin-5-7lineti}i)-3,4-dih7dro-lH"-qiiiDoliii-2-one;
i-(3-Pipera2in-l-"^-5-lrifuoromethyl-ben2:}d)-3,4-diKydro-lH-quinoHii-2-one;
l-(2-ChIoro-5-pipera2m-l-yI-beiizyi}-3,4-diIiydro-lH-quinolin-2-oiie;
l-{5-Ue&yi-5-piper22ki-1 -yi-henzyl) -3,4-diiiydro- lH-quiQolm-2-oae;
8-Me&oxy-l-[3-Methoi7-5-piperazdn-l-yi-benz5d)-3,4-dihydro-lH-quiiiolm-2-one;
l-(2-Methoiy"-3-pxperaz3n-l-yi-benzyI)-3,4-dahydro-IH-qumoIin-2-"One;
4-(3-Chloro-5-pipera2b-l-;d-beiiz)^)-7-metiiox7-4H-benzo[l,4]oxazin-3-one;
l-(3-Pipera2in--l-yl~benzyl)-l,3,4.5-tetraiiydrobenzo[b]a2epiii-2-otie;
1- (S-Methosy-S-piperazm- l-yl-benzyl)- lH-qumoHii-2-ODe;
l-ethyl]-pq)eraziii-l-yI}benzyI)-lH-qimiolin-2-oiie;
l-(3-{4-[2-(4-HuorophenyI>-etii^]-piperazm-l-yI}-5--meflioxybeii2yl)-lH-1 quinoIm-2-oiie;
l_{3-[4_(4,5-DibydrcKlH-imidazol-2-yl)-pipera2m-l-yl]-5-methos36ei^^ quiiio]iD-2-oiie;
l-[3-Methoxy-5-(4-pymmdin-2-yl-pipea^2m-]-yl)-berizyl]-lHqmiiolm^ .
l-(3-{4_[2-(4-FIuoro-pheiiyl)-etiiyi]-piperaziii-l-yI}-5-ine£hoxy--beii2yl>S-) metifaoxy-lH-c!umoliii-2-one;
l_(3-{4-[2-(4-FlxKjro-ph6noxy)-ethyl]-pipera2in4-yl}-5-methoxy-benzyl)-lH-qumolin-2-oiie; and
8-MeQioxy-l -C3-inethoxy-5- {4-[2-(4~methoxy-plienyI)-ethyI]-pipeiraCTi-1 -yl} -beazyl)-lH-qTmiolin-2-one,
5 (viii) The compotmd of (iv), wherdnXis -CH2-, Y is -CH2-; A is indolTlene or
pyrimidinyJen,- R^ is hydrogen and R^" is hydrogen.

(ix) The compound of (viii), A is 3,5-iD.doiyiene or 4,6-pyriiiiidiB7iKi.
(x) The compound of (ix), wherein said compound is selected from the group consistit^ o£
1 - (2-ChIoro-6-piperasin- l-yl-pyrimidin-4-^lmethyi)-3,4-diliydro- lH-qmnolin-2-one; and
l-{5-Hpera2m-l-yl-lH-iadol-3-)dmethrid)-3,4-dihydro-lH-quinolin-2-one.
(xi) A process for producing a compound of formula

wherein m, p, r, q, X, Y, A, V}> R*, R^ R^ R^ R^ R^ and R" are as defined in (i), com-prisii^
reacting a compound of the formula

wherein m, p, X, T, A, R\ R^ and R^ are as defined in (i), G is a leaving group, with a heterocyclic amine of the form"ola



(siv) A pharmaceutical composition comprisirig a feerapeutically effectire amount of at least one componnd of formula I or a piiarmaceutically acceptable salt thereof according to any one of (i) to (x) in admixture -with one or more pharmaceutically acceptable carrier for tke treatment of diseases.
(xv) The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 for use as medicament
(svi) Use of one or more compound of formula I or a pharmaceutically acceptable salt thereof accordii^ to (i) for the manxi&cture of a medicament for lhe treatment or prevention of a disease state that is alleviated by 5-HT6 agordst
(xvii) The use of (xvi), wherein the disease state comprises disorders of GNS. ("
(xviii) The use of (xrii), wherein the disease state is selected from psychoses, schizophrenia, manic depressions, neurological disorders, memory disorders, attention deficit disorder, Parkinson"s disease, amyotrophic lateral sclerosis, Aldieimer"s disease and Huntington"s disease.
{■six) The use of (xriii), ■ftierein the disease state comprises disorders of the gastrointestinal tract
Unless otherwise stated, tiae following terms used in tiais Application, including tiie
specification and claims, have the definitions given below. It must be noted that as used
in the specification and the appended daims, the singular forms "a", "an," and "the"
I include plural referents unless the context dearly dictates otherwise. (
"Agonist" refers to a compound that enhances the activity of another compound or receptor site.
"Alkji*" means the monovalent linear or branched saturated hydrocarbon moiety, consisting soldy of carbon and hydrogen atoms, having from one to twdve carbon " atoms. "Lower aflcjd" refers to an alkyi group of one to six carbon atoms (i.e., "Cj-
Cgalkyi"). Examples of alfcjd groups indude, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyi, tert-butjd, pentj^, n-hexyl, octyi, dodecyi, and fee like.
"Alkylene" means a linear satmrated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three, to six carbon ^ atoms, e.g., methylene, etii)dene, 2,2-dimethyiethylene, propylene, 2-methyiprop}dene, butylene, pentjdene, and the like.

"Alkenylene" means a linear ■ansatuxated divalent hydrocarbon radical of two to six carbon atoros or a braached saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., ethenyiene (-CH=CH-)^2,2-dimeth7^etheiiyleDe, propenyEene, 2-methyipTopenyLene, butenylene, paitenylene, and the like.
"Alkoxy" means a moiety of the formula -OR, wherein R is an alkyi moiety as defined herein. Examples ofalfcoxymoiefiesinclude,butarenotlimitedto,methoxy, ethoxy, isopropoxy, and the like.
"Antagonist" r^rs to a compoimd that diminishes or prevents the action of another compound or receptor site.
"Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of arj^ moieties include, but are not limited to, phen"jd, naphthyi, naphthalenyi, phenanthryi, fluorenyi, indenyi, pentalenyi, azulenyi, oxydiphen^d, biphenyl, mefhylenediphenyl, aminodiphenyi, diphen^dsulfidyi, diphenylsulfouyi, d^henyiisopropylidenyi, benzodio3an")d, ben2oftiranyi, benzodioxyiyi, benzopyranyl, benzoxazinyi, benzoxazinonyl, benzopiperadinyl, benzopiperazinyi, benzopyrrolidinyl, benzomorpholinyl, metiiylenedioxypheny], ethjdenedioxfplienyl, and the Hke, including partially hydrogenated derivatives thereof.
"Arjdene" means a divalent arjd radical wherein axyl is as defined herein. "Arylene" I includes, for example, ortho-, meta- and para- phen^dene (1,2-phenylene, 1,3-phenylene and 1,4-phenylene respectively), which may be optionally substituted as defined herein.
"Arylalkjd" and "Aralkyi", which maybe used interdiangeably, mean a radical
-R^R** where R" is an aDsyleine groiip and R^ is an aryl groiq) as defined herein; e.g., benzyl, phenylethyl, 3-(3-chloropheny5-2-methylpentyl, 2-(4-fiuorophenyi)-ethyl, 2-{4-> methoxyphenyi)-eth)d, and the like are examples of arylalkjd, the aryl portion of which may be optionally substituted.
"AryloxyaBcjd mean a radical -R^-O-R"" where R" is an alkyieae group and R"" is an aryi group as defined herein, the aryi portion of which may be optionally substituted. Exemplary aryiosyallTi indude 4-iuorophenoxyeth)d, 4-methoxypheno3:yethyl, and the 3 like.

"Cydoalkyl" means a monovalent saturated caibocydic moiety consisting of mono- or bicydic rings. Cydoalkyl can optionaEybe substituted witli one or more substituents, wherein eadi substituent is independently hydroxy, alkyi, alkoxy, halo, haloalkyl, amino, monoalkjdamino, or dialkyiaminOj unless otherwise spedfically indicated. Examples of cydoalkyl moieties indude, but are not limited to, cydoprop^ cydobutyl, cydopentji, cydohecyl, cydoheptyl, and die hke^ induding partially unsaturated derivatives thereof such as cycbhexen-jd, cydopentenyi, and the lii:e. .
"Cydoalfcjialkyl"* means a moiety of the formula -R"-R", where R" is alkyiene and R" is cydoalkyl as ctefined herein.
"CycloaJkoxy" means amoiety of fee formula-0-R." where R." is cycloalkyl as defined herein.
"Heteroalfcyl" means an alicyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of-OR", -^fR^^ aad-S(0)oR"* (idiere n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalfcyl radical is through a carbon atom, wherdn R" is hydrogen, acyl, alltyi, cf doalfc/l, or cydoalkyialfcylj R** and R^ are independentiy ofeadi other hydrogen, acyl, alkyl, cydoalbyl, or cydoalkjdalfcyi; and when n is 0, R"* is hydrogen, aikyi, cydoaBcji, or cydoaBcyialkyl, and when n is I or 2, R is alfcyi, cydoalkyl, cydoaBcyialk)^, amino, acjdamino, monoalkjdamino, or dialfcjdamino. Representative examples indude, but are not limited to, 2-hydrosyethyl, 3-hydroiypropyi, 2-hydroxy-I-hydroxymethjdethyl, 2,3-dihydrosypropyJ, 1-hydroxymetii-yiethyl, 3-hydroxybutji, 2,3-dihydrosybutyi, 2-hydroxy-l-methyiprop)d, 2-aminoethyi, S-aminopropyl, 2-methyisuLfon7ieth7i, aminosulfonylmetiiyl, aminosulfonyiethjd, aminosulfonjdprop}^, meth)damioosijlfon}dmethyl, mediylaminosulfonyietihyl, methyiaininosulfonTipropyi, and the like.
"Heteroaryi" means a monocydic or bicydic monovalent radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms sdected trom N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryi radical iviH be on an aromatic ring. The hetexoaryl ring may be optionally substituted as defined herein. Examples of heteroaryi moieties indude, but are not limited to, imidazolyl, oxazoljl, isoxazol;^, fhiazolyi, isothiazolyi, oxadiazoiyl, thiadi^wl^, pytz-nujl, fhienyl, beiiaothienyi, thiophenyi, fiiran^i, pyran^d, pyridyi, pyridinyl, pyridazyi, pyrrol^, pyrazol^ pyrimidyl, quinolmyl, isoquinoHnyi, benzofinyi, benzothiopheny], benzothiopyranyi, benzdmidazolyl, benzooxazolyl,

benzooxadiazol)^, benzothiazolyi, benzoliiaadiazol/l, bensopyranfl, mddlyX isoindol}^, txiazolyl, triazmyl, gmnoxaliiiTl, ptiiiayi, q-uinazoliayi, quinoHzin-yl, napbtiiyridmyl, pteridinyl, carbazoijd, azepinyi, i^azcpmji, acridin^ and tiie like, induding partially hydiogeaated derivatives thereof.
"Heteroarj"Jeue" means a drralent heteroaryi radical -wierein heteroaryl is as defined herein. "Heteroaiylene" maybe optionally substituted as defined herein. "Heteroarylene" includes, for sample, indolylene, pTtimidinyiene, and the like.
The terms "halo" and "halogen", which maybe used interchangeabty, refer to a substituent flnoroj chioro, bromo, or iodo.
"Haloalfcyi" means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloall^ include -CH;C1, -CH2CP3, -CHjCaa, perfiuoroaDfyl (e.g., -CFs), and the Bke.
"Heterocydoamino" means a saturated ring wherein at least one ring atom is N, NH or N-allqd and tiie remaining ring atoms form an alkyiene group.
"Heterocydyi" means a monovalent saturated moiety, conslstii^ of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxj^en or sulfur). The heterocydyl ring may be optionally substituted as defined herdn. Examples of heterocydyl moieties include, but axe not limited to, piperidin^, piperazinyi, homopiperazinyi, azepinyi, pyrrolidinyi, pyrazolidiny^, imidazolinyi, imidazoHdinyl, pyridin"^, pyridaidnyi, pyrimidinji, osazolidinjd, isoxazolidin)d, morpholinyi, thiazoUdinjd, isothiazolidin-j^, quinudidinyi, quinolinyi, isoquinolinTl, benzimidazolyi, tiuadiazolyiidinyi, benzothiazolidinyi, benzoazolyiidinyi, dihydrofur}d, tetrahydrofurji, dihydropyranyl, tetrahydropyranTl, thiamorphoUnyi, thiamorpholin^ulfoxide, thiamorpholin"jdsulfone, dihydroquinolinyi, dihydrisoquinoKnyi, tetrahydroquinolinyi, tetrahydrisoquinoHnyl, and the Ijke, induding partially unsaturated derivatives thereof
"Optionally substituted", when used in assodation with "aryi", "arylene", phenyl", "phenyiene", "heteroaryi", heteroaxylene or "heterocydyl", means an aryl, arylene, phenyl, phenyiene, heteroaryi, heteroaryiene, or heterocydyl which is optionafly substitiited independently with one to four substituents, preferably one or two substituents sdected from alkyl, cydoalfcjd,, cydoalkosy, cydoalkjdalkyi, beteroallqd, hydroxy^Ikjd, halo, nitro, cyano, hydroxy, alkoxy, anuno^ acjdamino, mono-aliyiamino, di-alkyiamino, haloalkyi, baloalkoxy, heteroalkyi, -COR (where R is hydrogen, alfcyi, phenyl or

pHenyialbyl), -(CR"R")n-COOR (-where n is an integer from 0 to 5, R" and R" are independently hydrogen or alJcyl, and R is Hydrogm, alkjd, cycloalkji, cycloalkylalkyl, pkenyi or plienylalkyl), or -(CR"R"\-C0NR.""R^" (where n is aa integer &om 0 to 5, R"
and R" are independently hydrogen or alkyl. and R"" and R"*" are, independently of each other, hydrogen, alkyi, cycloalkyU cycloaBcylaDiyl, phenyl or phenylalkyl.
"Leaving group" means the g-oup with the meaning conventionally associated vnih it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups indude, but are not limited to, halogen, alkane- or arjdenesulfonyloxy, such as methanesulfon^doxy, ethanesulfonyiosy, thiomethyl, benzenesiilfon^xy, tosyioxy, andthienyioxy, dihalophosphinoyloxy, optionally substituted benz^oxy, isopropyloxy, acylosy, and the like.
"Modulator" means a molecule that interacts "with a target The interactions include, but aie not limited to, agonist, antagonist, and the like, as defined herein.
"Optional" or "optionally" means that the subsequentiy described event or circnmstance may but need not occur, and that the description indudes instances where the event or drcumstance occurs and instances in whidi it does not
"Disease state" means any disease, condition, symptomi or indication.
"Inat organic solvent" or "inert solvent" means ihe solvent is inert under the conditions of the reaction being described in conjxmction therewith, induding for example, benzene, toluene, acetonitrile, tetrahydxofuran, NJ:^-dimethylformamide, chloroform, metiiyiene chloride or dicbloromethane, dichloroethane, diethyl ether, eth"jd acetatCj acetone, methyl ethyl ketone, methanol, etiianol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
"Pharmaceutically acceptable" means that which is useftd in preparing a pharmaceutical composition tt^t is generally safe, non-toxic, and neitiier biologically nor otherwise undesirable and indudes that which is acceptable for veterinary as well as human pharmaceutical use.
"Pharmaceutically acceptable salts" of a compound means salts that are phannaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound, Sudi salts indude:

add additioii salts foimed with, inorganic adds sudi as bydxodiloric add, hydrobromic add, sulfuric add, nitric addj phosphoric add, and tie like; or formed with organic adds such as acetic add, benzenesulfonicadd, benzoic, camphorsuLfonic add, dtric add, ethanesulfonic add, fumaric add, glucoheptonic add^ gluconic add, glutamic add, ^ycolic add, hydroxynaphtoic add, 2-hydTosyethanestilfonic add, lactic add, maldc add, malic add, malonic add, roandelic add, methanesulfonic add, mucoiiic add, 2-naphthaIenesuifonic add, propionic add, salicyKc add, succiiiic add, tartaric add, p-toluenesulfonic add, trimethyiacetic add, and the like; or
salts formed when an acuiic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases indude diethanolamine, ethanolanaine, N-meth"]dglucamine, triethanolarnine, tromethamine, and the like. Acceptable inorganic bases indude almnimim hydroxide, caldum hydroxide, potasstum hydroxide, sodium carbonate and sodium hydroxide.
The preferred pharmaceutically acceptable salts are the salts formed from acetic add, hydrodiloric add, sulphuric add, methanesulfonic add, maldc add, phosphoric add, tartaric add, dtric add, sodium, potassium, caldum, zinc, and magnesium.
It should be understood that all references to phannaceutically acceptable salts indude solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same add addition salt
The terms "pro-drug" and "prodrug", which may be used interchangeably herein, refer to any compound which releases an active parent dri^ according to formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula I are prepared by modifying one or more fonctional group(s) present in the compound of formula I in such a way that the modi£cation(s) maybe deaved in vivo to rdease the parent compound. Prodrugs indude compounds of formula I wherein a hydroxy, amino, or sulfliydryi group in a compound of Formula I is bonded to any group that maybe deaved in vivo to regenerate the free hydroxyl, amino, or sulfliydryi group, respectiv>^. Examples of prodrugs indude, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N>N-dimeth)daminocarbonyi) of hydroxy functional groups in compounds of formula I^ N-acyi derivatives (eg. N-acetyi) N-MannicH bases, Schiffhases and ensamnones of amino fonctional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde

fanctiona] groups in compoirnds of Formula I, and the Hke, see Bundegaard, H. "Design of Prodrugs" pl-92, Hesevier, New York-Oxford (1985), and the like.
"Protectfve group" or "protecting- group" means the grox^ which selectively" blods one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventioually assocb-ted with it in synthetic diemistry. Certain processes of tius invention rely upon the protective groups to block reactive nitrogen andior orj^en atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen protecting group" are used interdiangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyi (carbobenzyioxy, CBZ), p-metiioxybenzyioxj^rarbonyi, p-nitrobenzylosycarbonyl, tert-butoxycarbonyi (BOC), and the lite. The artisan in the art will know how to choOse a group for the ease of removal and for the ability to withstand the following reactions.
"Solvates" means solvent addition forms thzt contain either stoichiometric or non stoichiometric amoimts of solvent Some compounds have a tendency to trap a fixed molar ratio of solvent molecnles in the crystaBuie solid state, thus forming a solvate. If the solvent is vra-ter the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcokolate. Hydrates are formed by the combination of one or more molecules of water mik one of the substances in which the water retains its molecular state as H2O, such combination bein^ able to form one or more hydrate.
"Subject" means mammals and non-manunals. Mammals means any member of the mammalia class including, but not BxDited to, humans; non-himian primates such as chimpanzees and otiier apes and monkey spedes; farm animals such as catde, horses, sheep) goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals indude, but are not limited to, birds, and the like. The term "subject" does not denote a particular age or sex.
> "Ths-apeuticaEf effective amount* means an amount of a compound ihat, -when
administered to a subj ect for treating a disease state, is suffidsit to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and

rdative health of the subject, tie route and form of administratioii, the judgement of &e attending medical or veterinary practitioner, and other fectors.
The terms "Those defined above** and "those defined herein" -when referring to a variable incorporates hy reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any.
"Treating" or "treatment" of a disease state indudes:
(i) preventing the disease state, i,e. causing the clinical symptoms of the
disease state not to develop in a subject that may be exposed to or predisposed to the disease state, bnt does not yet experience or display symptoms of the disease state,
(ii) inhibiting the disease state, ie., arresting the development of the disease
state or its dimcal symptoms, or
(iii) relieving the disease state, ie., causing temporary or permanent regression of the disease state or its clinical symptoms.
The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents tmder appropriate conditions to produce the indicated and/or the desired product It should be appreciated that the reaction which produces the indicated and/or tiae desired product may not necessarily result directiy fi-om the combination of two reagents which were initiafly added, ie., there may bp one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated andj"or the desired product
In general, the nomenclature used in this AppUcation is based on AUTONOM v.4.0, a Beilsteia Institute computerized system for the generation of lUPAC systematic nomendature. For convenience, the lUPAC numbering of the positions of representative quinolinone compounds described herein is shown by the formula:

In embodiments of the invention wherein X is a heteroatom, the benzoxazinone numbering system is used herein as shown by the formula:


Ckeimcalstruttores shown herein were prepared using ISIS Tersioii2^. Any open valency appearing on a carbon, oxygen or nitrogen atom in tbe structures herein indicates the presence of a hydrogen.
The invention provides compounds of the formula I:

and pharmaceutically acceptable salts or prodrugs thereof,
w^rein:
m is from 0 to 4;
p is from 1 to 3;
q is from 1 to 3;
r is from 1 to 3;
A is aryiene or heteroarylene;
E is N or C;
X is O, S, or -CR"^R""- wherein R" and R^ each independently is hydrogen or a]iyl;

eac±L R^ independently is halo, allc)^, haJoaDtyl, hetsroalkyl, hydroxf, nitro, alkoxf, cyaao, -SCO)sR", -NR"R^ -C(=0)-NR=R^ -SOr-NR"R^-N(R=-C(=0)-R"" or -C(=0)-R", wherein s is &om 0 to 2 and R"" and R** eacij independentlf is hyixogen oi aUcyl;
Y is-(CRV)n--wherein n is 1 or 2 and R^ and R^ each ind^endentiy is hydrogen or altyi, or X and Y together may optionally form an alkenylene group;
R , R , R^, HJ, R^ and R^ each iadependeiitJf is hydrogen or aliyJ,- and
R^° is hydrogen, aUcyi, arylalfcjd, arjdoxyaUc^, heteroar^ or heterocydyi.
In embodiments of the invention where any of R\ R^ R^ R^ R^ R^ R^ R^ R^ R^", are aJkyt, they preferably are lower alfcyi, i.e. Ci-Qaifcyl, and more preferably Ci-04alfcyl In many embodiments of the invention wherein A is optionally substituted phenylene, A may be in a "meta" phenyiene or 1,3-phenyieue configm^tion with respect to the bemyiic carbon adjacent the quinoline 1-position and the piperazin}d moiety. Exemplary substituted phenyienes indude halophenyiene, haloallfTiphenyiene, alkylphenylene, alkoxyphenylene and alfcylHiedioxypbenyiene, In embodiments where A is heteroarylene, the heteroaiylene may be pyrimidinylene (ie., a divalent pyrimidinyl radical) or indol)4ene (divalent indolyl radical).
In embodiments of the invention where R"° is arylalkjd, R^° is preferably optionally substituted phenjdethyi such as 2-(4-fluorophenyl)-etbyi or 2-(4^metho3;yphenyi)-eth)i. "Where R^° is heteroaryi, it is preferably pyrimidyl sudn. as pyriniidin-2-yl. Where R"° is heterocydyi, it is preferably imidazolinj^ such as imidazolin-2-)d.
It should be understood that the scope of this invention encompasses not only the vaiious isomers which nmy exist hat also the various mixture of isomers which maybe formed. Furthermore, the scope of the present invention also encompasses solvates and 5alts of compounds of formula I.
" In many embodiments of the invention Y is -(CR"^R )n-, q is 2 and r is 2, such that
compounds of formula I may be represented by the formula le


wiierein m, n, p. X, A, E, R^ R\ R^ R*, R^ R^ R^ R*, R^ and V}° axe as defined kerein.
In certain embodiments of formula Icpis 1 and A is optionally substituted phenej^ene. In such, embodiments the compounds of the invention maybe represented by the formula I£

wherein t is &om 0 to 4, each R" individually is halo, aliyi, iwloalkyl, hydroxy, nitro. cyano or alkoxy, and m, n, X, E, RS R^ R^ R^, R^ R^ R^, R^ R^ and R^° are as defined herein. In certain embodiments t is 0 or 1 and R ^ is halo, alkyl, haloalkyi, cycloalkosy or alkoxy, and in spedfic embodiments R" maybe chloro, methyl, trifiuorometh"jd, mefeosy, cydohej:yiosy or ethosy. In certain embodiments t is 2 and the pair of R" groups together define an alfcjdene dioxy radical or moiety sudi as an ethylene diosy radical.
In certain embodiments, X is -CR^R^-, n is 1 and E is N, sudi that compomids of the invention may more specifically be of the formula Ig:


wiierein m, t, R\ K\ R^ R*, R^ R^ R", R^ R^ R^^ R", R^ and R^ are as defined h.erein.
In other embodiments of formula I, X and Y may optionally form an alkeo^ene group, and in specific embodiments X and Y may form an ethen^dene group of the formula;
-CH=CH-. The subject compomids in such embodiments may be more specificaliy represented by the formula V:

wherein represents an optional bond, and m, t, R^ &■*, R^, R^, R"", R*, R^ and
R^° aie as defined herein. In ^edfic embodiments of formula y, R*, R^ R^, R^, R^ R^ and "B}° are hydrogen, and liie optionally substituted phen)dene moiety is in a"meta" configuration (ie., a 1,3-phenylene configuration) with respect to the location of the benzfiic carbon proximate to the nitrogen at die 1-posi^on of the quinolinone ring system and the piperazinyl group. In such embodiments the compounds of the invention maybe represented by the formula H;











Another aspect of the mvention provides a composition comprising a tierapeutically effertire amount of at least one compound of formula I and a pharmaceuticallf acceptable carrier.
Yet another aspect of lie inTention provides a method for treating a central nerrous system (CNS) disease state in a subject comprising administering to the subject a therapeuticaliy effective amount of a compound of formula I. The disease state may comprise, for example, psydioses, schizophrema, manic depressions, neurological disorders, memor7 disorders, attention deficit disorder, Parkinson"s disease, amyotrophic lateral sderosis, Alzheimer"s disease or Huntii^on"s disease.
Still another aspect of the present inventaon provides a method for treating a disorder of the gastrointestinal tract in a subject comprising administering to the subject a tiierapeuticany effective amoimt of a compound of fotrouia I.
Another aspect of Ihe present invention provides a method for producing a compound of formula I.
Compounds of the present invention can be made by a variety of methods depicted in the illiistrative synliieiic reaction schemss shown and described bdow.
The starting materials and reagents used in preparing these compounds generally are either available from commercial supplia-s, such as Aldrich Chemical Co., oi axe prepared by methods known to those skilled ia the art following procedures set forda in references such as Heser and Fieser"s Reagents for Organic Synthesis; Wiley & Sons; New York, 1991, Volumes 1-15; Rodd"s Chemistry of Carbon Compounds, Hsevier Science Publishers, 1989, Volmnes 1-5 and Supplementals; and Organic Reactions, .Wley & Sons; New Yorl^ 1991, Volumes 1-40. The following synthetic reaction schemes are merdy illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to diese synthetic reaction schemes can be made and will be suggested to one skilled in the art havir^ referred to the disclosure contained" in this AppHcation.
The staxtiag materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not ) limited to, filtration, distillation, crystallization, chromatography, and the like. Sucii materials can be characterized using conventional means, induding physical constants and spectral data.

Unless specified to the contrarf, the reactions described herein preferably are conducted uiider an inert atmospiiere at atmospiieric pressure at a reaction teniperatiire range of from about -78 °C to about 150 °C, more preferably from about 0 "C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 °G.
Scheme A below illustrates one synthetic procedure usable to prepare compounds of &£ invention, wherein G is a leavii^ gKfup and may be tite same or different in &ach occurrence, and m, q, r, t, R^ R^ R*, R^ R^ R^ R^ R^° and R^^ are as defined herein. Specific examples of the procedure of Scheme A are provided in the following Experimental section.

SCHEME A
Numerous synthetic routes to partially hydrogenated quinolinones are known and ii^y be nsed in preparation of the subject compounds, The synthesis in Steps 1 and 2 of Scheme A represents the procedure r^orted by Paviaetal.., 7- Org. Chem. (1990)VDL

55(2), pp. 560-564. Briefly, in Step 1 an orttoQitrobenzaldeliyde ais alkylated via an aJdol reaction with a carbethozyalkylene triplienylpliospiioraDe (not s}iO"wn) or like agent to provide an aldol condensaticm prodnctb. Various nitro- substituted benzaldehydes usable in this step are commerdaHy available or can be prepared via well known techniques. For example, nitrobenzoic adds maybe reduced to the corresponding benzyl alcohol using borane or like reducing agent, and the benzyl alcohol then selectivdy oxidized to the corresponding benzaldehyde via pyridinium dilorochromate reduction as reported by Pavia et al., supra.
In Step 2, a cydization of aldol condensation product ^ Tinder reducing conditions yidds quinobnone£. This cydization maybe achieved, for ejcample, by hydrogenation in die presence of platinum catalyst
In Step 3, an N-aJkyiation is carried out by treatment of quinoHnone c with strong" base, such as a metal hydride under polar aprotic conditions, foDowed by esposure to alkylating agent d to provide an N-aliijdated quinolinone e. The leaving groups G of alkylating agent d, whidi maybe the same or different, are preferably bromo or other halo.
A cross-coupling amination reaction may then be utilized in Step 4 in wiiich. the N-alkyiated guinolinonee of Step 3 istreated with a heteroq"dic amine fin the presence of a palladium catalyst to displace leaving group G and yield a heterocydyl-substituted quinolinone YQ. This cross-coupling reaction may be adiieved via heating under uonpolar solvent conditions. Where R"" is hydrogen, BOC protection or other removable protection strategies may be used to protect fhe exposed nitrogen of heterocyclic amine f.
The substituted quinolinone VH produced in Step 4 represents a spedfic embodiment of compounds of formula I, discussed above, wherein X is —CH2-, Y is -OHR^-i n is 1, p is 1, A is optionally substituted phenylene, and E is N.
Numerous variations on the procedure of Steps 1-4 are possible and may be tised to provide various compounds of formula 1. One such variation useful for prepaxation of quinolinones wherein R^ is sensitive to or incompatible with the reducing conditions of step 2, involves reaction of the orthonitrobenzaldehyde a with "Meldrum"s ester" in die presence of trieth)4anmie and formic add to produce an aldol condensation product (not shown). The aldol condensation product can then be esterified and subject to cydization

by iieating in the presence of sodium dithionate to provide qmnolinone c. This particular procedure is described in Synthetic Communications-, Vol. 25 p. 3067 (1995).
In anQther variatioii, aUcjiatmg agent d used in the alkyiation of Step 3 may comprise a a-haloallcfl uaphdiji compound, a-IiaIoalkyIbiph.en7l compound, a-haloalkjdethyienedioxyphenjd compound, or other a-haloalkyiar^ compound. In other embodiments Step 3 may be canied out using a-haloalkyl heteroaryl compounds such as a-haloalfcjdpyridines, a-haloalkyithiophenes, a-haloalkjiindoles, a-haloalkyiethyienedioxyphenTi compounds, and the like. In the case of a-haloalkyi heteroaiTd compounds, iuitable protection group strate^es maybe employed to avoid unwantai heteroatom aJkjdation during tiiis step.
In certain embodiments, heterocydic amine f may be a piperazine of the formula:

(i.e., q and r each are equal to 2), such that the compound of formula I| is of formula Ig discussed above, witii R^ shown as hydrogen. Many substituted piperazines of this sort, including N-meth"jd piperazine and 3,5-dimeth.7ipiperaziQe for esample, are commercially available or prepared by wdl Icoown techniques and may be used in the procedure of Scheme A.
In other embodiments of the invention, Step 4 maybe omitted and Steps 5-7 carried out in place thereof. In Step 5, the N-alltylated quinolinone e prepared in Step 3 is litbiated via treatment with an aDqditbium reagent to provide a lithiated quinolinone g.
An alfcyiation may then b e carried out in Step 6 by reaction of lithiated quinolinone
f mth a heterocyclyl ketone h to effect formation of compound j. Heterocyclyi ketone h
may comprise, for KSample, an optionally substituted piperidinone or an optionally
substituted pyrrolidinone, both of "wiudi are commercially available or can be prepared
by well-knovm techniques. Where R^° is hydrogen, a BOC, allyl or o^er protection
group may b e used to protect the nitrogen heteroatom of ketone \. -"

Compound i may in turn be dehydrated in Step 7 and then optionally subject to reduction to proTide qumolinone derivatiye ^ In certain embodiments, dehydration of compound j may occur spontaneously. Quinolinone derivatiye ^ represents a specific embodiment of compounds of formula I wherein, wherein X is -CHr-, Y is -(CR.^R^)n-wifh n being 1 and R^ being hydrogen, p is I, A is optionally substituted phenylene, and E isCH.
Scheme B below illustrates another syn&etic procedure that may be used in preparation of compoundls of the invention, wherein G is a leaving group and may the saroeordiferoatin eadi occurrence, andm, n, q, r, t,R,!R,R,R,R,R,R,R and R^^ are as defin«i hereiii.

SCHEMES
Many synthetic routes to benzosazinones are known and maybe used in the preparation of the subject compounds for embodiments of formula I wherein X is O, and the sya&esis outlined in Steps I and""" "^"^"■^ »T.=mnlarv.

In Step 1 of Sciieme B, an ortlio nitroplienol j is reduced to an aniline or aminopiienoi k. This reduction may be carried ont under relativdy mild, aqueous conditions, using sodium dithionite or like mild redudng a^ent
A cyclization is then carried out in Step 2 to provide a benzozazinone compound m
from the aminophenol x generated in Step 1. Where n is 1, for exaroplej the
benzoxazinone m is a 2H-l,4-ben2oxa2in-3(4iH)-one, and where n is 2 the compound m
is a 2,3~Dih7dro-l,5-benzoxazepin-4(5H)-one. TTie cydization maybe achieved by
reaction of the aminophenol j vrith a 2-halQ add halide 1 (G is halo) such as chloroacetfl
ciiloride (to provide n= I and R^, R* as hydrogen), 2-chloropropionyi chioride (which
provides n = 1, R^ as meth"ji and R* as hydrogen), 3-chloTOpropionyl chloride (providing
n = 2 and R", R* as hydrogen), 2-chloroisobutyryL chloride (providing n = 1, R^ as isoprop^i and R* as hydrogen), 2-chloro-2-methyi[propionyl chloride (providing n = 1 and R^ and R* as methyl), and so on. Formation of benzosazinones in this manner can be achieved under relativdy mild polar conditions in the presence of a mild base, as described by Combs et al.; /. Med. Chem.; 33; 380-386 1990. The cyclization may also be achieved by reacting fe with a 2-hydroxyester under Mitsunobu reaction conditions, as described by Van Hess et ai in WO 01/14330. See also Heterocydes 1983, vol 20(8), pp. 1481-1485, for synthesis of substituted benzoxazinones.
In Step 3, an N-aEqdation of the benzoxazinone compound m is carried out by
treatment of compound m with a strong base under dry, polar aprotic conditions and
reaction with an a-haloalkj^ aryi compound n to provide the N-arjdalkyi-benzoxazinone
compound o. The haloaHcjd aryi compound n may comprise, for example, benzyl halide, f
3-haIo-3-phenylpropane, a-mefjiyibenzyi halide, or otter o-taloalfcyiphenyi halides according to the desired R and R^ substituent configuration.
The alkylation of Step 3 may also be carried out using a-haloaBcjd napthyl compounds, a-haloalk^iphenyi compounds or other a-haloalkylaryi compounds. In other embodiments Step 3 may be carried out using a-haloallcji heteroarji compounds such as a-haloalkylpyridines, a-haloallcjdthiophenes, a-lmloallqdmethylenedJoxyphenyl compounds, a-haloalkyiethylenediosyphenyl compounds, and the like. In the case of a-haioalkyi heteroaryl compounds, suitable protection group strategies may be employed to avoid unwanted heteroatom alkylation during this step.
A cross coupling amination reaction is tiien carried out in Step 4 wl^rein the N-arylalkyi- bemxpaziaone compound o is reacted with a nitrogen-containing heterocyde f

in the presence of a palladium catalyst to replace the leaving group G -with, a Heterocydyi group and provide tke iLeterocydyi-N-aiylalkyl-benzoxazinone compound Im. In many embodiments g and r are 2, such. tba.t the heterocyde compound f is a piperazine compound as described above io Example A. Where R^^ is hydrogen, BOC protection or other removable protection strat^es may be used to protect the esposed nitrogen of heterocydic amine £
The heterocydyl-N-aryialkyi-benzoxazinone compound ^ is a compound of formula I wherein X is O, Y is -(CR^R^)D-, p is 1, q and r are 2, A is optionally substituted phenyiene, and E is N. As in the case of Scheme A, many variations on the above procedure are possible and maybe used to prepare other compounds of formula I in accordance with the invention.
In ofiier embodiments of tiie invention, Step 4 of Scheme B maybe omitted and Steps 5-7 carried out in place thereof in the manner described above for Scheme A Thus, in Step 5, the N-allq^ted beuzoxazinone Q of Step 3 is hthiated via treatment widi allcylithium reagent as described-above for Sdieme A, to provide a Hthiated benzoxazinone pt. An alkyiation may then be carried out in Step 6 by reaction of lithiated "benzoxazinone ^ with heterocydyi ketone h to yidd compoimd a- Heteiocydyi ketone h maybe an optionally substituted piperidinone or an optionally substituted pyrroHdinone as noted above, and a suitable protection strategy for the nitrogen heteroatom may be employed where R"° is hydrogen. Compound g may in turn be dehydrated in Step 7 and then optionally subject to reduction, to provide benzoxazioone (Le., quinolinone deiivatrve) In.
The compound la is a compound of formula I wherein X is O, Y is -(CR^R")n-, p is 1, q and r are 2, A is optionally substituted phenyiene, and E is C. It is again noted that variations on the above procedrure may be used to make other compounds of formula I. Suda Variations will suggest liiemsedves to those skilled in the art and are considered to be within the scope of "fliis disdosure.
In still other embodiments of the invention, specific compounds of formula I may be prepared according to Ihe procedure shown in Scheme C, wherdn G is a leaving group " and may the same or different in. each occurrence, and m, q, r, t, R\ R^, R*, R^, R , !R^ R , R^" and R" are as defined herein.


In Step lofSchemeQtetralone £15 converted to a tetraloneoximes. Thisniaybe aiiieved by treatment oftetralonerwitiihydrox^ainine under aqueous conditions with Keating.
The oxime s of Step 1 undergoes a ring expansioii rearrangement in Step 2 to provide a tetrahydrobenzoazepinone t. Tbe rearrangement of Step 2 may be carried out by heating oxime £ in the presence of polyphosphoric add-In Step 3, tiie tetrahydrobenzoazepinone t of Step 2 is N-alkylated via treatment wjtii alkjdating agent n to yield an N-aIfc)dated tetrahydrobenzoazepinone u. The alkylation of this step may be effected by treatment of tetrahydrobenzoazepinone t with metal hydride, together with alkylating agent n, imder polar aprotic conditioiis. Various alkyiatirig agents maybe usedinfbis step as described above according to particuiar compounds of formula I that are desired,
i A cross-coupling airdnation reaction is used in Step 4 "whereiu N-alfcjdated
tetrahydrobeazoazepiEione u is treated wilit heterocyclic amine fin the presence of base, trialkyiphospidne and a palladium catalyst as described above for Schemes A and B, to

provide tetxaiiydroberLZoazepiiioiie la- Various lieterocydic amines may be used in this step as related above, to provide ^^ous compounds of formula I in accordance with, the inventioii.
Tetraiiydrobeiizoazepinone Ig is a compound of formula I in accordance with the invention wherein X u -CH2-, Y is -(CH2)2-, p is 1, A is optionally substituted phenyl, and E is N.
Otiier compounds of the invention toay be prepared by omission of Step 4, with Steps 5-7 carried out instead. In a manner similar to that described above foi Scheme A and Scheme B, in Step 5 the M-alkjdated tetrahydrobenzoazepinone ji is Hthiated via ■ treatment wili allcylithium reagent to provide a Uthiated tetrahydrobenzoazepinone v. An alkjdation may then be carried out in Step 6 by reaction of Hthiated tetrahydrobenzoazepinone x with heterocydyl ketone ^to yield compound vr, which in turn can be dehydrated in Step 7 and lien optionally subject to reduction to provide tetrahydrobenzoazepinone l£.
The compound Ig is a compound of formula I wherein X is -GH2-, Y is -(CHalj-, n is 2, R^ and R^ are hydrogen, p is 1, A is optionally substituted phenyl, and E is C. It shoidd again be noted tlKit variations on the above procedure may be i^&d to make other compounds of formula I, as wiU be readily apparent to those skilled in the art
More specific details for producing compounds of formula I are described in the Examples section below.
The compounds of the invention have selective 5-HT6 receptor affinity and as such are expected to be useful in the treatment of certain central nervous system (CNS) disorders such as Parkinson"s disease, Huntington"s disease, anxiety, depression, manic depression, psychosis, epilepsy, ohssssbre compulsive disorders, migraine, Alzheimer"s disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia and bulimia, panic attads, attention deficit hyperactivitf disorder (ADHD), attention deficit disorder (ADD), withdrai^"al from drug abuse such as cocaine, ethanol, nicotiiie and benzodiazepines, sdiizophrenia, and also disorders associated with spinal trauma and/or head injury such, as hydrocephalus. Such compounds are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such ftmctional bowd disorder.
The pharmacology of the compounds ofthis invention was determined by art recognized procedures. The in vitro techniques for determining the afSnities of test

compounds at the 5-HT6 receptor in radioligand binding and fmictional assays axe described in Example 4.
The present invention iodudes pharmaceutical compositions comprising at least one compound of the present inyention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate tiiereof, together with at least one pharmaceutically acceptable carrier, and optionally odier therapeutic and/or proph)dactic ii^edients.
In general, the compounds of the present invention mQ be administered in a therapeutically effective amount by any of tiie accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, liie indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in tiie art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this AppHcation, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
In general, compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub¬lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intiavenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage r^unen which can be adjusted according to the degree of afOiction.
A compound or compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, maybe placed into tiie form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or wiliiout additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of tiie adive ingredient commensurate witii the intended daily dosage range to be employed. The pharmaceutical compositions maybe employed as solids, such as tablets oi filled

capsules, semisolids, powders, sustained release forraulations, or liquids sudi as Solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1} miSigrain of active ingredient or, more broadly, about 0.01 to about one bundred (100) milligrains, per tablet, are accordingly suitable representatiTe unit dosage forms.
The compounds of the present invention may be formulated in a wide variety of Oral administration dosage forms. The pharmaceutical comipoaitions and dosage forms may comprise a compound or compounds of the present invention or phaimaceuticaHy acceptable salts thereof as the active component The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, piUs, capsules, cachets, suppositories, and disperable granules. A solid carrier may be one or more substances wbidi may also act as diluents, flavourir^ agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture witii the finely divided active component In tablets, the active component generally is mixed with the carrier having the necessary biadiag capacity in smtable proportions and compacted in the shape and size desired. The powders and tablets preferably contain fi:om about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carb onate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tr^acanth, meth)dcdlulose, sodium carboxymethylcdlulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to indude the formulation of the active compoimd with encapsulating material as carrier, providing a capsule in wBidi the active component, with or without carriers, is surrounded by a carrier, whidi is in association wit±L it Similarly, cachets and lozenges are induded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administratioiL
Other forms suitable for oral administration indude liquid form preparations induding emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or soHd ■ form preparations whidi are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying ^ents, for example, such as ledthio, sorbitan monooleate, or acada. Aqueous solutions can be pr^ared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing-

the finely diTided active component in water with Yiscxius material, sudi as natural or synthetic gums, resins, methyicdlulose, soditim carboxymethylcdlulose, and. other well known suspending agents. Solid form preparations indude solutioBs, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, bakers, artifidal and natural sweeteners, dispersants, thickeners, solnbilising agents, and tie like.
The compounds of the present invention maybe formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and maybe presented in unit dose form in ampoules, pre-filled springes, smaD Tolume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqxieous polyethylene glycoL Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include prop)dene ^ycol, polyethylene ^col, V^et^le oils (e,g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wettingi emulsifying or suspending, stabilizing and/or di^ersing agents. Altemativelyj the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization &om solutioa for coxistitiition before use wifh a suitable vehicle, e.g., starile, pyrogen-free water.
The compounds of the present invention may be fommlated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thidceuing and/or gelling agents. Lotions maybe formulated with an aqueous or oxlybase and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thidcening agents, or coloring agents. Formulations suitable for topical administration in the mouth indude lozenges comprising active agents in a flavored base, usually sucrose and acada or tragacanth; pastilles comprising the active ingredient in an inert base sudi as gdatine and glycerine or sucrose and acada; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
3 The compounds of the present invention may be formulated for administration as
suppositories. A low mdting was, such as a mixture of fetty add glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogaieous mixture is then poured into cocvenioit sized molds, allowed to cool, and to solidify.

The compounds of the present invention may be formiilated for vaginal administxation. Pessaries tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers zs are known in the art to he appropriate.
TTie compounds of the present invention may be formulated for nasal administration." The solutions or suspensions are appHed directly to the naasal cavity by , conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In liie latter case of a dropper or pipette, this may be achieved by the patient administering axi appropriate, predetermined volume of the solution or suspension. Inthecaseof a spray, this may be achieved for example by m^ns of a metering atomizing spray pump.
The comppunds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (C?C), for example, dichlorodifluorometlmne, triciilorof[uorom.ethane, or dichlorotetiafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a sur&ctant such as leciliun. TTie dose of drug may be controlled by a metered valve. Altemativdy the active ingredients maybe provided in a form of a dry powder, for example a powder mis of the compound in a suitable powder base sudi as lactose, starch, starch derivatives such as hydrosyprop^^ethyl cellulose and polyvinyipyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for e^mple in capsules or cartridges of e.g., gelatine or blister packs from vAich the powder may be administered by means of an inhaler.
When desired, formxilations can be prepared, with enteric coatings adapted for sustained or contioHed release administration of the active ingredient For example, the compounds of the present invention can be fonnulated in transdermal or subcutaneous drug dehveiy devices. These deUvery systems are advantageous when sustained release of the compound is necessary and when patient compHance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skia-adhesive soHd support The compound of interest can also be combined with a penetration enhancer, e.g., Azone (i-dodecylazacycIoheptan-2-one). Sustained release delivery systems are inserted subaitaneously into the subdermal layer by surgery or

injection. Tkesiibdeiindiinplants encapsulate the compaundin a lipid soluble mernbrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
The pharmaceutical preparations are preferably in unit dosage forms. In such, form, the preparation is subdivided into unit doses containing appropriate quantities of the active component The unit dosage forro can be a packaged preparation, liie package coataining discr^e quantities of preparation, sncii as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage fonn can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of aay of tiiese in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in RemingtOTV The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19t3i edition, Easton, Pennsyivania. Representative pbarmaceutical fonnulations containing a compound of the present invention are described in the Examples below.
EXAMPLES
The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting &e scope of lie invention, but merdj as being illustrative and representative tiiereo£
Preparation 1
3-Bromo~5-metho3cy-benzyl bromide
The synthetic procedures described in this Preparation were carried out according to the process shown in Scheme D.


10.5 Grams (55mmole) ofmetKyi3-methoS7-4-ammobaizoate was dissolvedin 30nil methanol, and 3.0 ml bromine (SSmmole) in 20ml acetic add was added dropwise st room tanperature. The solution was stirred for tiiree hours at room temperature and die solvents were evaporated under reduced pressure. The residue was treated with sodium bicarbonate solution and the product was ffltered and air-dried to yield 16.5 grams of metjij^ 3-bronio-5-mediosy-4-aniinoben2oate.
Step 2:
Methyl 3-bromo-5-methosybenzoate


A 500 ml round bottom flask fitted wilii overhead stkiing was charged with 16.5 grams (SSminole) of metbyl 3-bromo-5-methoxj"-4-aniiiioben2oate in 80 ml ethanol, 15 ml sulfuric acid and 20EQ1 acetic add. The solution was chilled in an ice bath and 6.6gms (95mmoIe) of sodium nitrite in 30ml water was added dropwise while maintaining the tHiiperature below 10"*C, After stirring an additional 25 minutes, 100 ml of 50% hypophosphoric add was added and the mixture was stirred cold for 2 hours. The reaction mncture was diluted with 500 ml water, extracted with ether, and then evaporated under reduced pressure to give i3.S grams of meth}i 3-bromo-5-methoxybenzoate as a reddish oiL

13.5 Grams (55mmole)) Methyl 3-bromo-5-metiho37benzoate was dissolved in ether and cooled in an ice bath, 33 m] of IM lithium aluminum hydride was added dropwise. The reaction mix was then quenched cautiously by addition of sodium sulfate decahydxate, then water, and solid residue vras removed by filtratiorL The ether was separated and evaporated under reduced pressure to give llgm.s of 3-bromo-5-methosy benzyl alcohol as a white soHd.
Step 4
S-Bromo-S-methoxv-benzyi bromide


11 Grams (Slmmole) of 3-bromo-5methQxy benzyl alcoKolwas dissolved in 100 ml meihyieiie chloride and cooled in an ice-bath. 2.0 nil (20mmole) of phosphonis tribromide was added dropvrise to this soiution at room temperature, and the mixture was allowed to stir for 10 minutes. Saturated sodium bicarbonate solution was then added, and llie mixture was extracted with ether and washed with sodium bicarbonate solution. Evaporation of the ether yielded 12 grams of 3-Bromo-5-metioxy-benzyl bromide as a white solid.
Using the procedure of Example 1 with the appropriate substituted methyl benzoates, the foUowing representative benzyl bromide compounds were also prepared:
3-bromo-5-h7droxy-benzyl bromide;
S-bromo-S-ethoxy-benzsd bromide;
3-bromo-5-trifluoromethyl-benzyi bromide
3-bromo-5-meth)d-ben25d bromide;
3-bromo-4-methoxy-benrpi bromide;
3-bromo-5-cycIopent)4oLX7-ben2:j4 bromide;
3-bromo-2-chloro-ben2)d bromide; and
7-bronJo-5-bromometh)4- 12,3-dih7dro-benzo [1,4] dioxine.
Example 1
l-f"3-Methoxy:5-piper^jn-l-yJ-be]igyi}-3)4~dihydro-lH-qiimoline-2-one
The syntiietic procedures described in this Example were carried out according to the process shown in Scheme E.


3,4-Diliydro-2{ lH)-quinolmone was purchased from Aldiich Chemical Co. (Cat No. 41,593-6) and used wiliiout pmification in this step. 0.45 grams of 3,4~dihydro-2(lH)-quiiiolinone (3.0 mmole) was dissoh"ed in 15 ml dimethyifonnamide and cooled in an ice bath. 0.2 grams (4.5 mmole) of sodium hydride (60%wt. in oil) was added to this solution, and after 5 minutes 0.84 grams 3-bromo-5-methosy-benz7lbromide (3 mmol) was added lihereto all at once. The mixture was stirred at ice bath temperature for I hour and then quenched by addition of 1% hydrochloric adi The reaction mix was extracted -with eth-jd acetate, which was evaporated under reduced pressmre to give an oil, which was chromatographed with medium pressure duting using 10% eth"jd acetate in

Kesanes to yield O.Sgrams of solid 4-(3-bromo-5-metiio3:y-beii27i)-3,4-dili7dro-lH-qmnoline-2-one.
Step 2

O.S grams (2.2 mmole) of 4-(3-bromo-5-methoxy-ben2yl)-3,4-dili7dro-lH-quinoline-2-one, togetiier with 0.44 grams of 1-Boc-Piperazine, 0.025 grams (0.11 mmole) of palladium (II) acetate, 0.023 grams (O.OU mmole) of tri-t-butyl phosphine and 0.23 grams of sodium-t-buto3dde) were added to 20 ml of xylenes. The solution was
heated to 110°C under argon for 4 hom-s. The resulting dark mixture was filtered through celite, the solvent evaporated, and the residue chiomatograghed via medimn pressure eluting with 20% e&yi acetate in hexanes to yidd 0.4 grams of solid l-(3-methoxy-5-pipera2in-l-yI-benz;)d)-3,4-dihydro-lH"-quinoIine-2-one as a white soHd.
Step 3

The Boc-protecting group was removed firom l-(3-methox7-5-piperazin-l-yi-benzyl)-3,4-dili7dro-lH-quinoline-2-one by warming the 0.4 grams of product from Step 2 with 5 ml triflouroacetic add. Excess trifluoioacetic add was evaporated under reduced pressure and the trifiuoroacetete salt was crystallized from etit)^ acetate / diethyl

ether to yield 0.35 grams of l-(3-metiioxf-5-piperazm-l--yi--ben27])-3,4-dili7drD-lH-qtiiQoliiie-2~oiie, M+H - 352.
Using th.e above procedure, tut replacing 3-bromo-5-rrie1iioxy-benzyIbronude in step 1 with the appropriate benzyl bromides prepared as described in Preparation 1, the following compounds were also prepared:
l-(3-Pipera2in-l-jd-ben2:jd}-3,4-dih7dro-IJ?-quinolin-2-one;
l-(4-Metboxf-3-pipera2in--l-yi-beQzyi)--3,4-dihyidro--LH"-qmno]iii-2-one;
1- (3-CHoro-5-pipera2in- l--yl-benz7l)-3 j4--dibydro- lH-quiiioiia-2--one;
1- (3-CydopentjdoJ7-5-piperaziii- l-yl-benzjd) -3,4-dihydro- lH-qmnolin-2-on^
l-(3 -Hydroxy-S-piperazin- l-yi-benzyi)-3,4-diIiydro- lH-qTiinolin-2-one;
1- (3-Ethoxy-5-piperarirt- l")^-benzyl)-3,4rdihydro- lH-qiiinolin-2-ooe^
1 -(7-Pipera2in- l-7l-2,3-dihydro-ben2o [1,4] dioxin-S-ylmethyi) -3,4-dih.ydro- IH-quinolin-2-one;
1 -(3 -Piperazin-l-)4-5-trifuoron:etiiyi-be!az)^)-3,4"dih7iiro-lH-qi2inolin--2-one,"
l-(2-Chloro-5-piperaziii-l-yi-beiizjd)-3,4-dihydro-lK-qmiioKn-2-one;
l~{3-Methyl-5-piperazm-l-7l-ben2yi)-3,4-dihyd]:o-lH-qmnolin-2-one;
1 -(2-Metboxy-3-pipera2in- l-7i-beiizjd)-3,4-dihydro-lH-qmnolin-2HDne;
l-(3-Methoxy-5-pipera2in-l-yl--benzyi)-3,4-dibydro-iH-qmnolin-2--one;and
1 -(3-MeiiiD37-5-pipera2an-l -7l-benzj^)-lH-quiiiolin-2-one.
Using the above procedure, but replacing pipexaziae in step 2 witb 1-methyipiperazine, l-[3-niethosy-5-(4-inethyipiperaziii-l-yi)-benzyl]-3,4-diliydro-lH-quinolin-2-one was prepared.
Using the above procedure, but replacing 3,4-dih7dro-2(lH)-quinoiinone in step 1 with 5-di]oro-3,4-dih7droquinoIin-l-one prepared accordmgto the procedure reported in Bioorganic &Medidnal ChsmistryLetters (2000), Vol. 10(14), pp. 1559-1562, and

using 3-bromo-2-ct!loro-benz)d "bromide m step 1, tbe compound 6-Chioro-l-{3-cblorD-5-piperaziii--l-)d-ben2:jd)-3,4-diliydro~lH-quinolin-2-one was prepared.
Using the procedure of Example 1, but replacing 3,4-diliydro-2(lH)-qmiioHiione in step J with S-methoxy-S.^-diJiydroqLiinoIin-I-one prepared according to the procedure reported m Journal ofOrgamc Clismistry {1990), Vol. 55(2), pp. 560-564, the compound 8-me&oxf-l-(3-Me{hoxy-5-piperazin-I-yi-beiizy-I)-3,4-dihy-dro-Ii?-quinolin-2-one was prepared.
Also using the proceduxe of Ixample 1, but replacing 3-bromo-5-metiioxy-benzyibromide respectivdy with S-bromo-S-bromomethyi-lH-indole and 4-BromD-6-bromometh7i-2-cbloro-pyrimidine, tihe compounds l-(5-Piperazin-l-yl-lH-indol-3-ylniethyl)-3,4-dihydro-lH-quinolin-2-one and l-(2-Chloro-6-piperazin-1 -yl-pyrimidin-4-)^ethyi)-3,4-dihydro-lH-quinolin-2-one were prepared.
Using the above procedure, but repladr^ piperazine in step 2 with the appropriate substituted piperazine, Ihe following compotmds were prepared:
1 - (3-Methoxy-5-{4-[2-(4-methosy-phenyl)-ethyl]-piperazin-l-yl}benzyi)-IH-qmnoilin-2-on^"
l-(3-{4-[2-(4-Huorophenyi)-eliiyi]-piperazin-l-yi}-5-methoxybenzyi)-lH-quinoHn-2-one;
l-{3-{4-(4,5-Ditiydro-lH-imida2ol-2-yl)-pipera2in-l-)d]-5-inetiioxyben2yi}-lH-quinolin-2-one;
1 - [3-MethQxy-5- (4r-pyriinidin-2-yl-pipera2in-1 -yl)-benzyil - lHqmnolin-2-one;
l-(3-{4-[2-(4-Huoro-phenyi)-e-tihyl]-piperazm-l-yi}-5-methosy-benzyi)-8-methoxy-lH-quinoIin-2-one;
l-(3-{4-[2-(4-Fluoro-phenoxy)-eth-)d]-piperazin-l-yl}-5-naedioxy-ben2yl)-lH-quinolui-2-onee; and
8-Methorf-X-(3-medioKy-5-{4-[2-(4-methoxy-pheQ7])-eth7i]-piperasin-l-yl}-benzyi) - lH-qmnoliii-2-one.
•pxamptp ?. 4"f3-Cbloro-S-piperazin-l-vl-benzvl)-7-methosy-4H-beiizo[li-i1nya7in-3-nne

The synthetic procedures described in this Example were carried out according to the process shown in Scheme P. In liis example, the 7-methox7-l,4-hen20sazni-3-one used in Step 1 was prepared by the well loiown procedure described in Heterocycles (1983), Vol. 20(8),pp. 1481-1485.

0.5 grams of 7-metfaoxy-l,4-benzoxazm-3-one (2.8 mmole) was dissolved in 10 ml of dimethyiformamide and cooled in an ice bath. 0.17grams (3.5mmole) of sodium hydride (60%wt inn ofl) Was added, and after 5 minutes O.Sgrams (2.9 nomole) of 3-bromo-5-chIoro-benzyibromide was added all at once. The mixture was stirred at ice bath temperature for 1 hotir, and then quenched by addition of 1% hydrochloric add. 1 The product was extracted with eth}^ acetate, that was evaporated under reduced pressure to give an oil which was chromatographed via medium pressure eluting with

10% ethyl acetate in hexanes toyidd 0.9 grams of"4-(3-bromo-5-chIoro-benz7l)-7-methosf-4f:r-beii2o[l,4]oxa2iD-3-one as a wiiite solid.

The deprotection of 4-[3-chloro-5-{4-Boc-piperaziii-l-7l)-benz7l]-7-methosy-4H-benzo [1,4] oxa2in-3-one was cairied out using tbe procedure described above in Example 1, Step 3, to yield 0.55 grams of 4-(3--Chloro-5-piperazin-l-)d-beii2;)4)-7-metiioxy-4H"-beii£o[l,4]oya7.m-3-one, M+H = 389.
Example 3
l-f3-Piperazin-l-yl-benzvl1-13,4.5-tetraliydrobenzorbla2epia-2-one
The synthetic procedures described in this Esaniple were carried out according to the process shown in Scheme G.



and the mjrtiire was extracted "with SO mL ethyl ether. The organic phase was washed with 10 mL saturated sodium chloride, dried (MgSOi) and concentrated under reduced -pressure. The residue was recrystallized from ether/hesane to give l,3,4,5-Tetrah7dro-benzo[b]azepin-2-one, 0.682 g, m.p. 141-142°.
Step 3

To a stirred mixture of 0.1 g (4 mmole) sodium hydride and 0.75 g (3.0 mmole) 3-bromobenzyl bromide in 5 mL dimeth"jdfbrmamide was added 0.438 g (2.72 mmole) solid l,3)4,5-tetrah7dro-benzotb]azepin-2-one. The mixture was cooled in a water bath, then it was stirred at 23° for 1 hr. The solvent was removed under reduced pressure and the residue vras partitioned between 30 mL ethyl acetate and 5 mL water. The organic phase was washed with 5 mL water, 5 mL saturated sodimn chloride, dried (mgS04) and concentrated under reduced pressure. The residue was recrystallized from hexane to provide the title compotmd, 0.658 g, m.p. 81-82".
Step 4

Amisture of 0.5 g (1.51 mmole) l-(3-bromo-benz)4)-Z^,4,5-tetrahydro-benzo[b]azepin-2-one, 0.203 g sodium tert-butoxide, 0.04 g (.16 mmole) tri-tert7butyi

pKosphine, 0.04 g (.16 mmole) palladium(II)acetate, and 0.3 gpiperazin-l-yl carbosylic acid tert-hutyl tstcr in 5 mL xylene was heated at 105° under N; for 1.5 hrs. The mixture was diluted "witH 5 ml ethyl ether and then filtered through a pad of 10 g silica gel 230-400mesh. 4-[3-(2-OKO-2,3,4,5-tetrahydro-benzo[b]a2epin-l-7linethyl)-phen7l]-piperazine-i-carboxyiic add tert-birtyi ester was eluted with 20% ethyl acetate/hesane to yield 0.64 g of a heavy syrup. M+H = 436.
Steps

A solution of 0.6 g (1.38 mmole) 4-[3-(2-oxo-23,4,5-tetrahydro-benzo[b]azepin-l-ylmeth"}d)-phenyi] -piperazine-l -carboxylif- add tert-butyi ester in 3 mL trifluoroacetic arid vras concentrated under reduced pressure. The residue was partitioned between 10 mL saturated sodium carbonate containing 1 mL 5% sodium hydroxide and 35 mL ethyl acetate. The organic phase was dried (MgSOi) and concentrated undo: reduced pressure. The residue was conyerted to the maleate salt and recrystallized from metiianol/ethji acetate to provide l-(3-Pipera2in-l--ji-benzyl)-l,3.4,5-tettahydrobeDZo[b]a2epin-2-one
as a maleate salt, 0.346 g, m.p. 149-150°.
Example 4 Formulations
Pharmaceutical preparations for delivery by various routes are formulated as shown in the following Tables. "Active ingredient" or "Active compound" as used in the Tables means one or more of the Compounds of Fonnula L








adjust pH. The nasal spray fonnulatioiis may be delivered via a nasal spray metered pump typically delivering about 50-100 microliters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.
Example 5
Radioligand hi"nding studies
This example illustrates in vitro radioligand binding studies of compound of formula I.
The bindir^ activity of compounds of this invention in vitro was determined as follows. Duplicate determinations of Hgand affinity are made by competing for binding of [TJ]LSD in cell manbranes derived from HEK293 cells stably expressing recombinant human 5-HT6 receptor. This cell line was prepared by the method described by Monsma et aL, Molecular Pliarmacohsy, Vol 43 pp. 320-327 (1993).
All determinations were made in assay buffer containing 50 mM Tiis-HQ, 10 mM MgS04,0.5 mM EDTA, 1 mM ascorbic add, pH 7.4 at 37 "C, in a 250 microliter reaction volume. Assay tubes containing [^H] LSD (5 nM), competing ligand, and membrane were incubated in a shaking wra.ter bath for 60 min. at 37 °C, filtered onto Packard GF-B plates (pre-soaked with 0.3% PEI) using a Padcard 96 wdl cell harvester and washed 3 times in ice cold 50 mM Tris-HCL Bound [^H] LSD was determined as radioactive counts per minute using Packard TopCounL
Displacement of [3H]LSD from the binding sites was quantified by fitting concentration-binding data to a 4-parameter logistic equation:
, . ,. , , f Bmax-basal
where HiU is the Hill slope, [Ugand] is the concentration of competing radioligand and IC50 is the concentration of radioligand producing half-masimal specific binding of radioligand. The ^edfic binding window is the difference between the Bmax and the basal parameters.
Using the procedures of this Example, compounds of Formula I were tested and found to be selective 5-HT6 antagonists as shown below:


Pxamplft fi
CAgnitinn F.n>ianr.frmffnt
The cogiiition-enliandng properties of compoimds ofthe invention may be in a model of animal cognition: the object recognition task model. 4-montii-oldmale"TOstar rats (Charles River, The Netherlands) were used. Compounds were prepared daily and dissolved in physiological saline and tested at tJiree doses. Administration WES always given i.p. (injection volume 1 ml/kg) 60 minutes before Tl. Scopolamine hydrobromide was injected 30 minutes after compound injection. Two equal testing groups were made of 24 rats and were tested by two experimenters. The testing order of doses was detejmined randomly. The experiments were performed using a double bHnd protocol. M rats were treated once witii each dose condition. The object recognition test was performed as described by Ennaceur, A., Delacour, J., 1988, A new one-trial test for

neurobiological studies of memory in rats. 1: Behavioral data. Behav. Brain Res. 31.47-59.
While the present invention has been described with reference to the specific embodiments thereof, it ahould be -understood by those sIdUed in the art that varioiis changes may be made and equivalents may be substituted without departing fom the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to Ihe objective spirit and scope of the present invention. All such modifications are intended to be within ttie scope of the claims appraided hereto



and pharmaceutically acceptable salts or prodrugs thoreof,
-wherein:
m is from 0 to 4^
p is from 1 to 3;
q is from 1 to 3;
r is from I to 3;
A is optionally substituted arydene or optionall)i" substituted heteroarylene;
BisNorC;
X is O, S> or -CR"R""- wlierein R* and R"* each independenfly is hydrogen or alkyij
each R^ independently is halo> alkyl, haloaHcylj heteroalkyl> hydroxy, nitro, alkoxy, cyano. -5C0)X -NR*=R^ -CC^O^NR^**. -^02-NR"R"*-NCR"=-C(=O)-R"* or -C(-0>-R", wherein s U from 0 to 2 and ^ and R^ each independently is hydrogen or
Y is -CCR^R")a- irfierem n is 1 or 2 and R" and R" each independently is hydrogen or aDcyi, or X and T together fonn an alkenyicnc group;

R*, R^, R^> R", R", and R" each ind^endently is hydrogen or alkyli and R" is hydrogen, aUkyi, aryialkyi, arjioxyalkji, heteroarj^ or heterocydyi.
2. The compound as claimed in daim 1, herein said compound is of the formula:

whenan m, p. X, Y. E, K\ R^ R^ R*, R^ R^ R^, R^ R** and R"° arc as defined in claim 1;
A is arylene or heteroarylene which are optionally substituted by the sustituents selected fiom alkyl, cycloaUj^I, cycloalkjlalkyl, heteroaHcyl, hydroxyallQrl, halo, nitro, cyano, hydroxy, alkoxy« amino, acjdamino, mcmo-alkylamino, di-alkylamino, haloalkj^, haloalkoxy, hetcioalb^ -CO^ (whoe R is hydrogm, aUcyl, phenyl or phenylaUcyl), -(CR"R*%-CC)OR (where n is an integer from 0 to 5, R" and R" are independently
hydrogen or alkyl, and R is hydrogen, alkyl, cycloaBq^, cycloaH^lalkyl, phenyl or phenylalkyl), or -1, phenyl orphenylalkyl
3. The compound as claimed in daim 2, wherein said compound is of the formula:


wherein X, Y, A, E, R^ R"*, m and n are as defined in daim 1.
4. The compound as claimed in daim 3. vAerein
XisOor-CHj-!
y -(CH2)n- wherein n is 1 or 2, or -X-Y- is -CH=GH-;
A is pheni^en^ indolylene, or pyrimidinylen optionally substituted by the substituents accorduig to daim 2;
EisN;
K" is halogen, alkox)r; and
R"" is hydrogen, alfcyl,, arylalk)^, arj^oxyalk^ heteroaryl or heterocyd]^.
5. The compound as claimed in daim 4, wherem R" is diloro or methoxy; R" is hydrogen, metiiyl, 2-{4-fluorophcnyl)-ethyi, 2-C4-methoxyphen)d)-etii)i, iimda2oIin-2-)4 or pyrimidin-2-yi} A is 1,3-phen^ene optionally substituted by the substituents according to daim 2,
6. The compound as claimed in daim 5, v^erein A is halophenyiene, haloalkjdpheiij^ene,
alk)dpheaylene, alkoxyphen^ene or alkylenedioxyphenj^ene.
7. The compound as claimed in ^^^^ 6> wherein said compound is selected fixim the
group consisting of:
l-(3-Piperazin- l-yl-benzyi)-3,4-dihydro- IH-quinolin-Z-one;
l-C4-Metiioxy-3-pipera2in-l-yl-benzjd)-3,4-dihydro-lH-quinoHn-2-one;

l-(3-CWoTO-5-pip«a2Jn-l-7iL-benzyi)-3,4-dih7dio-lH-qvmiolin-2-oae;
l-(3-Methoxy-5-pipera2in- l-yi-benz)d)-3,4-dihydro- iH-quinolin-Z-one;
e-Oiloro- l-(3-chloro-5-piperaan-l -]rt-benzyl)-3,4-dihydro- lH-qumolm-2-one;
l-C3-Cyclopent)doxy-5-pipera2in- l-)1-benzyl) -3,4-dihyciro- lH-quinolm-2-one;
l-(3-Hydrox7-5-piperazin-l -yi-benzyl) -3,4-dihydro- lH-quinolin-2-one;
l-(3-Ethoxy^5-piperazin-l-yl-benzyi)-3,4-dihydro-lH-qtimolin-2-one;
1- [3-Mcflica!y-5-(4-meth7ipiperazm-1 -yi)-benz)4]-3,4-dihydro-lH"-qumolin-2-one;
i
l-(7-Piperaziii- l-yl-2,3-daiydro-benzo[l,4] dio3dn-5--jdmeth^)-3,4-daiydro-lH"-qmnolm-2-one;
l-(3-Piperazm-l -)^-5-triftiorometliyi-benzyI)-3,4-dihydro- lH-quinolin-2-one;
1 -(2-Cliloro-5-piperazin-1 -^-benzi4)-3,4-dihydro- lH-quinoIm-2-one;
l-(3-Meth)i-5-piperazin-l-yi-benzyi)-3,4-dihydro-lif-quinolm-2-onej
8-Meliioiy- l-(3-Metiioxy-5-piperazm- l-)^-benzyi)-3,4-dihydro-lH-quinolin-2-one;
l-(2-Methoxy-3-piperazin-l-yi-beiizj4)-3,4-dihydro-lH-qumoliii-2-on^
4-C3-CWoro-5-piperazin-l-5d-benzjd)-7-metho:iqr-4H-benzo[l,4]oxazm-3-on«
l-(3-Piperazm-l-)d-bcnzjd)-l,3,4,5-tetrahydrobeii2o[b]azepm-2-one;
l-C3-Methoxy-5-piperadn-l-yi-benz)dl)-lH-qumoHn-2-one;
I-(3-Methoxy-5- {4-t2-(4-methoxy-phenyl)-etiiyl]-piperazm-1 -yl}ben2yl)-l H-qiunolin-2-one;
H3-{4-[2-(4-niiorophenyI)-ethyl]-pipera2m-1-yl}-5-methoxybenzyl)-lH~ quinolm-2"Cme;
1- {3-[4
1-[3-Mofhoxy-5-(4-pyrimidin-2-yl-piperazm-1-yO-ben2yl]-lHqmnolm-^
l-(3- (4-[2-(4-FhxorD-phenyl)-eth.yi]-piperazm-1 -yl} -5-methoxy-beQ2^)-8-methoxy-lH-qmnolin-2-ono;
l-(3- {4-[2-(4-FIuorD-phraoxy)-ethy1]-piperazm-1 -yl} -S-mefhoxy-benzyl)-1H-quinolin-2-one; and
8-Methoxy-l -(3 -methoxy-5- {4-[2-(4-methoxy-phenyl)-eGiyl]-piperazm-1 -yl) -benzyl)-lH-qumolm-2-one.
8. The compound as claimed in claim 2, wherein m = 0, X » -CHj-,
Y = -CHr. p « 1. R*. R", R^ R". R*. R"and Pt"" - hydrogen and A -
indolytene or pyrimidlnytene.".
9. TTie compound as claimed in daim 8, A is 3,5-indolylene or 4,6-pyrimidin5^en.
10. The compound as claimed in daim 9, vrfierein said compound is sdected from the
gioup consistii^ o£
l-(2-Chloro-6-piperazin- l-)"J-pyrinudin-4-^meth)"l)-3,4-dihydro- lH-quinolin-2-on^and
l-(5-Pipera2in-l -j^- lH-indol-3-)dmethyI)-3,4-dihydro-1 H-quinolin-2-one.

wherein m> p, r, q, X, Y, A, R\ R^ R^ R", R^ R", R" and R"° are as defined in cUi|n I, comprising;
reacting a compound of the formula




wherein m, p. r, q, X, Y. A. S}, R*, R^ R^ R", R", R" anji R"" are as defined in claim 1.
13. The compound of formula I or a phannaceutically acceptable salt thereof
according to claim l.wheneva-prepared by a process according to claim 11 or 12.
14. A pharmaceutical composition, comprising as an active ingredient the compound
of formula I as claimed in claim 1 along with the pharmaceutically acceptable carrier.

Documents:

2206-chenp-2005 abstract duplicate.pdf

2206-chenp-2005 abstract.pdf

2206-chenp-2005 claims duplicate.pdf

2206-chenp-2005 claims.pdf

2206-chenp-2005 correspondence others.pdf

2206-chenp-2005 correspondence po.pdf

2206-chenp-2005 description (complete) duplicate.pdf

2206-chenp-2005 description (complete).pdf

2206-chenp-2005 form-1.pdf

2206-chenp-2005 form-18.pdf

2206-chenp-2005 form-26.pdf

2206-chenp-2005 form-3.pdf

2206-chenp-2005 form-5.pdf

2206-chenp-2005 pct.pdf

2206-chenp-2005 petition.pdf


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Patent Number 228012
Indian Patent Application Number 2206/CHENP/2005
PG Journal Number 10/2009
Publication Date 06-Mar-2009
Grant Date 27-Jan-2009
Date of Filing 09-Sep-2005
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address 124 renzacherstrasse, CH-4070 Basel,
Inventors:
# Inventor's Name Inventor's Address
1 HARRIS, Ralph, New III 65-D Clinton Street, Redwood City, CA 94062,
2 REPKE, David, Bruce 406 South Temple Drive, Milpitas, CA 95035,
3 STABLER, Russell, Stephen 1360 HIGHLAND DRIVE, BOULDER CREEK, CA 95006,
PCT International Classification Number C07D 215/22
PCT International Application Number PCT/EP04/02340
PCT International Filing date 2004-03-08
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/453,574 2003-03-11 U.S.A.